In this fiscal year we have found that the ER-mitochondrion interface is important for increasing cellular bioenergetics by utilizing an anti-apoptotic protein Bcl-xL to enhancing the Ca2+ signaling between the ER and mitochondria. The synopsis is as follows. Non-apoptotic functions related to cellular localization are emerging for the Bcl-2 family. Bcl-xL, in particular, has been hypothesized to stimulate bioenergetics by regulating Ca2+ signaling at the ER. However, the functioning of Bcl-xL specifically in direct ER to mitochondrial Ca2+ transfer, through type 3 inositol 1,4,5-trisphosphate receptors (IP3R3), has not previously been investigated. Here we found a significant fraction of Bcl-xL in CHO cells exists in clustered form at the ER-mitochondrion interface or MAM (mitochondria-associated ER membrane) where it interacts with IP3R3 to enhance mitochondrial Ca2+ signaling and alter bioenergetics. Particularly, Bcl-xL enhanced mitochondrial Ca2+ transients upon thapsigargin (Tg)-induced ER Ca2+ depletion, while concomitantly reducing cytosolic Ca2+ release. Consequently, enhanced TCA cycle activity was observed in Bcl-xL overexpressing cells, which was further increased after prolonged Tg insult. This action is the result of Bcl-xL translocation to the MAM, which is the first known observation of Bcl-xL translocating during a non-apoptotic stress event. Our results suggest the MAM is a critical cell-signaling junction whereby Bcl-xL might have evolved to include multiple functionalities. One role being to facilitate cellular metabolism to promote normal cell functioning, and the second task being to prevent the initiation of apoptosis by increasing the bioenergetics capacity of the cell.